The disclosure is in the field of tissue engineering and medicine.
Collagen is present in many organisms. Collagen has evolved as the premier, load-bearing molecule in vertebrates and is responsible for sustaining tremendous forces within the human musculoskeletal system. Collagen is also the structural molecule of choice in a variety of other specialized connective tissues including blood vessels, cornea, fascia, periosteum sclera and skin. Unfortunately, when collagenous tissues fail and then fail to repair, the results can drastically affect patient mobility, increase the severity of other pre-existing conditions and ultimately, shorten life expectancy. Though significant effort has been expended to “tissue-engineer” natural grafts to replace damaged or diseased load-bearing extracellular matrices (ECMs) such as ligament, tendon and cornea, no clinically viable constructs have been produced. We currently have limited methods to repair or replace compromised, load-bearing collagenous tissues. Very little is known about the mechanisms which govern the organization and morphology of collagen during synthesis by fibroblasts in vivo, for it is the loss of or damage to organized collagen that is often irreparable. For example, the inability to reproduce collagenous structures de novo is attributable to a poor understanding of how fibroblastic cells control connective tissue production (Cowin, S. C., J Biomech Eng, 2000. 122(6): p. 553-69; Cowin, S. C., J. of Non-Newtonian Fluid Mechanics, 2004. 119(1-3): p. 155-162). Without a model from which to draw insight about control of collagen fibrillogenesis in vivo, tissue engineers rely heavily on seeded cells to direct the production of matrix, with limited success.
The fibril forming collagens in vertebrates (type I, II, III, V, XI) are the primary proteins responsible for bearing loads in blood vessel, bone, cartilage, cornea, intervertebral disk, ligament, sclera, skin and tendon. Degeneration of or damage to collagenous load-bearing structures continues to significantly diminish the quality of life of millions of individuals. Intervertebral disc degeneration can lead to lower back pain, which costs the United States more than $100 billion dollars per year. (Nagda, et al., Clin Orthop Relat Res, 2010. 468(5): p. 1418-22; Katz, J. N., J Bone Joint Surg Am, 2006. 88 Suppl 2: p. 21-4). There are as many as 175,000 ACL repairs performed annually in the U.S. at an estimated cost of 0.5 to 1.0 billion dollars. (Lyman et al., J Bone Joint Surg Am, 2009. 91(10): p. 2321-8). Collagen degradation in cartilage secondary to osteoarthritis will adversely affect the lives of more than 80% of Americans over 75 years of age and more than half of Americans over 60. (Arden, N. and M. C. Nevitt, Best Pract Res Clin Rheumatol, 2006. 20(1): p. 3-25). Tendon ruptures, aortic aneurysms, and keratoconus in the cornea are ultimately due to collagen network failures. There are also many collagen-related diseases due to genetic mutations, including Ehlers-Danlos syndrome, Bethlem myopathy, Alport syndrome, Knobloch syndrome, osteoporosis (some cases), osteogenesis imperfecta, arterial aneurysm and rheumatoid arthritis (autoimmune). For all of these conditions, there are few satisfactory treatments.